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Sleep-Related Traits and Attention-Deficit/Hyperactivity Disorder Comorbidity: Shared

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Sleep-Related Traits and Attention-Deficit/Hyperactivity Disorder Comorbidity: Shared medRxiv preprint doi: https://doi.org/10.1101/2020.09.13.20193813; this version posted September 14, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Sleep-related traits and attention-deficit/hyperactivity disorder comorbidity: shared genetic risk factors, molecular mechanisms, and causal effects Authors Marina Xavier Carpena¹, Carolina Bonilla²,3, Alicia Matijasevich¹,², Thais Martins-Silva¹, Julia P. Genro4, Mara Helena Hutz5, Luis Augusto Rohde6, Luciana Tovo-Rodrigues ¹ Affiliations ¹Post-Graduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Brazil; ²Department of Preventive Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil; ³ Population Health Sciences, University of Bristol, Bristol, United Kingdom. 4 Programa de Pós-Graduação em Biociências, Universidade Federal de Ciências da Saúde de Porto Alegre,Porto Alegre, Brazil 5Federal University of Rio Grande do Sul, Department of Genetics, Porto Alegre, Brazil 6 Federal University of Rio Grande do Sul, Department of Psychiatry, Child & Adolescent Psychiatry Unit,Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil; Corresponding authors: Marina Xavier Carpena – [email protected]; Luciana Tovo-Rodrigues – [email protected] 1 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.09.13.20193813; this version posted September 14, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Abstract Study Objectives: To evaluate the level of shared genetic components between attention- deficit/hyperactivity disorder (ADHD) and sleep phenotype, common pathways between them and a possible causal relationship between traits. Methods: We used summary statistics of the largest genome-wide association studies available for ADHD and sleep-related phenotypes including insomnia, napping, daytime dozing, snoring, ease getting up, daytime sleepiness, sleep duration and chronotype. We estimated the genomic correlation between ADHD and sleep-related traits using cross-trait LD-score regression and investigated potential common mechanisms using gene-based cross-trait metanalyses and functional enrichment analyses. The causal effect between the sleep related traits and ADHD was estimated with two sample Mendelian randomization (TSMR), using the Inverse Variance Weighted method as the main estimator. Results: Positive genomic correlation between insomnia, daytime napping, daytime dozing, snoring, daytime sleepiness, short and long sleep duration, and ADHD were observed. Insomnia, sleep duration, daytime sleepiness, and snoring shared genes with ADHD, which were involved in neurobiological functions and regulatory signaling pathways. The TSMR approach supported a causal effect of insomnia, daytime napping, and short sleep duration on ADHD, and of ADHD on long sleep duration and chronotype. Conclusion: Our findings suggest that the comorbidity between sleep phenotypes and ADHD may be mediated by common genetic factors with an important role on neuronal signaling pathways. In addition, it may also exist a causal effect of sleep disturbances and short sleep duration on ADHD, reinforcing the role of these sleep phenotypes as predictors or early markers of ADHD. 2 medRxiv preprint doi: https://doi.org/10.1101/2020.09.13.20193813; this version posted September 14, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Keywords: ADHD, genetics, sleep, circadian rhythm, neurodevelopment, Mendelian randomization 3 medRxiv preprint doi: https://doi.org/10.1101/2020.09.13.20193813; this version posted September 14, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Statement of Significance Our findings suggest that the comorbidity between sleep phenotypes and ADHD may be linked to common genetic factors with an important role on neuronal signaling pathways. They also show that a causal effect of sleep disturbances and short sleep duration on ADHD may exist, reinforcing the role of these sleep phenotypes as ADHD early markers, being able to predict the disorder. This study adds important information about the relationship between sleep, circadian rhythm, and ADHD since it raises new questions about the complexity of the phenomenon involving them and may also provide new treatment insights in this research field. 4 medRxiv preprint doi: https://doi.org/10.1101/2020.09.13.20193813; this version posted September 14, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Introduction Attention-deficit/hyperactivity disorder (ADHD) is one of the most common and highly heritable neurodevelopment disorders worldwide 1,2. Sleep disturbances and circadian disruption are common comorbid medical conditions that have been receiving growing attention in recent investigations. Several studies have shown that individuals affected by ADHD present higher prevalence of sleep and circadian disruptions than controls 3,4. In childhood, poor sleep quality is a frequent trait, being present in about 55–75% of children with ADHD 5–7. In adults sleep problems are also significantly associated with ADHD, being present in 60-80% of adult individuals with ADHD 8–10. Also, delayed sleep phase disorder, a circadian rhythm sleep-wake disorder, affects 73-78% of patients with ADHD in both childhood and adult life 3,11,12. Although the relationship between ADHD and sleep-related phenotypes may emerge from a complex environmental and genetic context, the potential mechanisms underlying the comorbidity, as well as causal relationships, are still not completely understood. Core clock gene impairment may link both conditions. In mice, modulation of the expression of the Clock Per1/2 and c-Fos genes in the brain while under methylphenidate and atomoxetine treatments was observed 13–15, and in zebrafish, the per1b-/- mutation was able to reproduce an ADHD mimic behavior 16. The alteration of the expression of these genes led to changes in norepinephrine and dopamine regulation, which are important neurotransmitters for both sleep regulation and ADHD symptomatology 17–19. In humans, expression and candidate-gene studies have supported a role of the CLOCK, PER2, BMAL1 and CSNK1E genes as potential links between sleep/circadian traits and ADHD 20–25. However, to the best of our knowledge, a broader investigation of shared genetics from a genomic perspective has not been performed to date. The direction of the association and whether there is a causal effect are unanswered questions and hot topics of a current debate in the field 26. Sleep deprivation and sleep problems are known to mimic or aggravate ADHD symptoms, and to regulate emotion, cognition and 5 medRxiv preprint doi: https://doi.org/10.1101/2020.09.13.20193813; this version posted September 14, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. behavior 3,4. On the other hand, ADHD-like behaviors may also lead to altered patterns of sleep 26,27. Early sleep disturbances predicting ADHD in the future are supported by longitudinal evidence 28–32. In addition, the opposite direction, in which ADHD may precede sleep disturbances and sleep deprivation is also reported in the literature 33–35. Thus, studies exploring causal relationships with different designs may contribute important evidence to better understand this relationship. Evidence about genetic etiologies for ADHD and sleep related traits has considerably increased in the last five years. Recent genome wide association studies (GWAS) have reported novel genes associated with sleep and circadian phenotypes, besides some already uncovered via candidate gene studies or animal models. Therefore, we were able to identify genome-wide markers associated with insomnia 36,37 daytime dozing 36, daytime napping 36, snoring 36, ease getting up 36, daytime sleepiness 38, chronotype 36,39 and sleep duration 36,40,41. Likewise, a powerful GWAS study was recently published, describing the first top-hits for the ADHD disorder 42. The recent publication of GWAS studies for sleep, circadian and ADHD phenotypes allows for the understanding of potential shared genetic and molecular mechanisms between sleep disturbances and ADHD, the dissection of possible differences in the association between specific sleep traits and ADHD, as well as the investigation on causality and the direction of this association. In this study we used the genomic data of the largest GWAS
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